Biol. Pharm. Bull. 28(9) 1578—1584 (2005)

Amino acids are one of the most important molecules in living organisms, and most of them have a chiral carbon at the a-position. In the higher animals, a large part of the naturally occurring amino acids is the L-form, and the stereoisomers (D-amino acids) had been believed to be rare. However, especially in the last decade, several D-amino acids were found in mammals including humans, and their distributions, functions and origins have gradually been clarified. In the frontal areas of the mammalian brain, a relatively large amount of D-serine (D-Ser) was found, and this D-amino acid is thought to be an endogenous agonist to the glycine site of the N-methyl-D-aspartate (NMDA) receptor. D-Aspartic acid (D-Asp) was localized to the endocrine tissues and is considered to have regulatory effects on various hormones. The D-alanine (D-Ala) amounts have also been reported to change in the case of diseases. Though the D-amino acids are being noticed as the candidates of physiologically active substances, the determination of most Damino acids is difficult because their amounts in mammalian tissues are extremely low and various interfering substances are present in the tissues. In addition, their functions, origins and regulation mechanisms still remain unknown for the most part. In this short review, we describe the current progress on the methods to determine D-amino acid in mammalian tissues including our recent reports. Using the methods, we determined D-leucine (D-Leu) and D-proline (D-Pro) in various regions of the mouse brain, and the detailed tissue distributions of these D-amino acids in the mammalian brain have been demonstrated for the first time, in addition to the distribution of D-Asp, D-Ser and D-Ala. Concerning the regulatory mechanisms of D-amino acids, we focused on the D-amino-acid oxidase (DAO, EC. 1.4.3.3), which catalyzes the oxidative deamination of D-amino acids to form the corresponding a-keto acids. This enzyme is widely observed in creatures, and most of the vertebrates have DAO in the kidney, liver and brain. Since the oxidation by DAO is one of the major regulatory pathways of Damino acids, it is important to investigate the effects of DAO activity on the amounts of naturally occurring D-amino acids in mammals. In this review, we present the tissue distributions of D-Asp, D-Ser, D-Ala, D-Leu and D-Pro in the brains of the mutant ddY/DAO mice lacking DAO activity, and control ddY/DAO mice having normal DAO activity.